ABSTRACT In the past decade, Uganda seen increases ? as large as 10-fold ? in the number of people who use drugs (PWUD) and the risk for HIV transmission through shared injection equipment, a common practice in this setting with low access to clean equipment. HIV prevalence among PWUD has been estimated to be as high as 45%, highlighting the importance of widescale access to HIV treatment and prevention for PWUD, including oral pre-exposure prophylaxis (PrEP). PrEP was integrated into HIV prevention guidelines in Uganda in 2016 and PEPFAR funding has been supporting targeted rollout to key populations, including PWUD. However, <250 people currently accessing PrEP have identified as PWUD, indicating a large gap in prevention and an opportunity to optimize PrEP delivery for PWUD. For PWUD living with HIV, antiretroviral treatment has been integrated into medication assisted treatment (MAT) programs and needle and syringe exchange programs (NSP), by leveraging providers who empathize with addiction and have experience combating stigma associated with drug use. We hypothesize that a similar approach can be done for PrEP by integrating PrEP delivery into MAT and NSP programs and we proposed a staged approach to conduct formative work and refine two integrated programs (PrEP + MAT and PrEP + NSP), to pilot these programs and assess PrEP uptake, retention, and adherence and to conduct costing research to directly inform policy guidance. Our work will be conducted with attention to several constructs within the Consolidated Framework for Implementation Research and grounded in a participatory approach with members of the largest harm reduction network, police force, and PWUD in Uganda as project advisors. Specifically, we aim to: 1) conduct qualitative research to explore preferences for HIV prevention services and willingness to use/prescribe PrEP among PWUD and providers of a) oral PrEP and b) services for PWUD in Kampala, Uganda; 2) refine programs for community- based NSP + PrEP and facility-based MAT + PrEP; 3) compare PrEP uptake, retention, and adherence when PrEP is integrated into community-based NSP versus facility-based MAT to PWUD; and 4) estimate the programmatic costs and conduct budget impact analysis for integrating PrEP into our MAT and NSP programs. Impact. The proposed work will provide robust evidence about how to optimize integrated harm reduction and PrEP delivery to PWUD in Uganda and similar settings. With direct engagement from members of the Ugandan Ministry of Health on our investigative team, our findings will be immediately useful for policy guidelines and to guide programmatic scale-up. This work will be relevant to the US and globally as a demonstration of co-located harm reduction and HIV prevention services for PWUD and it will provide some of the first data on PrEP adherence and retention among PWUD.